Traumatic brain injury (TBI), principally as a result of impaction on the intact closed skull, occurs in vehicular incidents, falls, acts of violence, and sports accidents. TBI is the leading cause of death and disability in the United States, with an annual incidence rate of 1.5 million. Of these, 50,000 die acutely, over 230,000 are hospitalized, and 80,000 experience long term disability. TBI affects people of all ages with most survivors suffering chronic, life-long disabilities with varying degrees of dependence. Currently, there are no therapies to treat TBI that have been demonstrated to improve functional outcomes like memory performance, which if the patient survives, is the most important clinical characteristic of a successful therapy. The lack of therapeutic intervention for a public health issue of this magnitude constitutes a healthcare crisis. We have recently demonstrated that the addition of exogenous apolipoprotein-E, or peptides derived from apoE's receptor binding domain, can significantly reduce inflammatory responses in the brain and in the periphery. Mice given TBI and then treated with COG133 at 30 minutes following head injury exhibited faster recovery times and their performance on behavioral tests recovered to pre-injury levels, whereas the behavior of head-injured saline treated mice never returned to preinjury levels of performance. In Phase 1 we systematically modified the apoE 130-150 peptide compound and successfully defined the minimal and essential residues that retain binding and anti-inflammatory activities. These data support a model where COG 133 assumes the structure of an amphipathic alpha helix that appears to be required for anti-inflammatory activity. Going beyond Phase 1, we have created COG 1410, a significantly modified and improved compound as disclosed herein. In Phase 2, we propose to test the hypothesis that the 3- dimensional structure and resistance to specific proteolytic degradation will further enhance activity in TBI, blood brain barrier penetration and therapeutic window of selected derivatives of COG1410. These studies are necessary to acquire the pre-clinical pharmacology needed to declare a clinical lead for Phase 2B studies of pre-clinical toxicology to support an IND application and Phase 3 human clinical trial studies to support an NDA application with the FDA.